This application addresses broad Challenge Area (14: Stem Cells) and specific Challenge Topic (14-NS-101: Reverse Engineering Human Neurological Disease). Viral or plasmid introduction of a transcription factor quartet is proven a powerful strategy to trigger reprogramming somatic cells into induced pluripotent stem (iPS) cells without the need of embryos or eggs. However, genetic manipulation using transgenes represents a serious hurdle to the use of these iPS cells for therapeutic application. While reactivation of trangenes could lead to tumorigenesis, leaky expression of transgenes may inhibit iPS cell differentiation, increasing the risk of immature teratoma formation. One way to solve this problem is to identify small molecules that induce endogenous pluripotent regulators without gene transfer. Furthermore, generation of iPS cells using existing technology by viral transduction or plasmid transfection of the reprogramming factors is a process with very low efficiency. The main goal of this research is to derive transgene-free human iPS cells using small molecules and to identify compounds that enhance reprogramming efficiency. This study will lead to the development of new methods for the derivation ofpluripotent human stem cell lines with high efficiency and open a new avenue to generate patient- and disease-specific pluripotent stem cells. These chemically derived iPS cells will become valuable tools for developmental biology, drug discovery, and regenerative medicine. PUBLIC HEALTH RELEVANCE: Chemical derivation of human iPS cells in virus-free and transgene-free means will open a new avenue to generate patient- and disease-specific pluripotent stem cells with high efficiency. These genetically unmodified iPS cells will be applicable in stem cell-based cell replacement therapies for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and brain injuries.